Manufacture of aminoquinolines



United States Patent This invention relates to improvements in themanufacture of ar-arninoquinolines. More particularly it relates toamination of 8-quinolinol with an ammonium salt of sulfurous acid in thesubstantial absence of free ammonia.

The preparation of ar-aminoquinolines and especially 8-aminoquinoline bythe Bucherer Reaction in which 8- quinolinol is reacted with ammoniumsulfite and ammonia under pressure is well known. This synthetic method,when carried out on a small scale, e.g., in the laboratory, is reportedto give almost quantitative yields. Because of the relative ease ofpreparation of 8-quinolinol as compared with 8-chloroquinoline or8-nitroquinoline, the Bucherer technique has been the preferred mode ofpreparing S-aminoquinoline. However, as the batch size is increased,certain unforeseen difficulties arise which cause the yield to drop. Themajor difliculty in the manufacture of S-aminoquinoline in full scaleequipment results from corrosive attack of the pressure equipment used,by one or more of the reactants. Even in stainless steel equipment,etching and severe pitting as well as moderate crevice attack, all ofwhich are evidences of corrosion, were noted when attempts were made toaminate 8-quino1ino1 with ammonium sulfite and free ammonia. In ordinarysteel equipment, the yield of 8-aminoquinoline fell to below 25% oftheory.

It is, therefore, a principal object of this invention to devise animproved process for the preparation of araminoquinolines.

Another object is to devise a process for the preparation ofar-aminoquinolines wherein corrosion of the equipment is practicallynil.

Still another object is to devise a process for the manufacture of8-aminoquinoline which is economical to operate and utilizes readilyavailable equipment.

These and other objects and advantages ancillary thereto will be evidentfrom the following description of my invention.

It has now been discovered that ar-aminoquinolines can be prepared inexcellent yields by heating an ar-quinolinol and a salt of sulfurousacid in which at least one valence of the sulfurous ion is satisfied byammonium and the other by ammonium, or an alkali metal (e.g., sodium orpotassium) or an alkaline earth metal (e.g., magnesium, calcium,strontium or barium). The reaction is carried out under moderatepressure, preferably in a stainless steel autoclave, at a temperatureabove 100 C., preferably between 140 and 160 C. This amination step,which is carried out in the absence of free ammonia, results in yieldsof excellent quality ar-aminoquinoline in excess of 75% of theory.Equally important, the corrosive attack of the metal equipment, which ischaracteristic of the known processes in which free ammonia is used, isgreatly reduced in ordinary steel equipment and is effec tivelyeliminated in stainless steel equipment.

Although the improved process is of particular benefit and interest inthe production of S-aminoquinoline from 8-quinolinol, this technique isapplicable also to the preparation of ar-aminoquinolines in generalwhich may contain additional substituents such as lower alkyl (e.g.,methyl, ethyl, butyl, hexyl, etc.) lower alkoxy (e.g., methoxy, ethoxy,isopropoxy, hexoxy, etc.) sulfamyl (e.g., sulfonamido, N-methylsulfonamido, N,N-diethyl sulfonamido) and the like substituents.Quinolindiols also can be used to prepare the correspondingaminoquiuolinols and diaminoquinolines although mixtures of suchproducts are usually obtained which are sometimes diflicult to separate.

As typical of the ar-quinolinols which can be used to producecorresponding ar-aminoquinolines, the following are mentioned:

S-quinolinol 6-quinolinol 7-quinolinol 2-m ethyl-8- quinolinol6-ethyl-8-quinolinol 6-methyl-5-quinolinol 6-isopropyl-5-quinolinol4-methyl-6-quinolinol 5-butyl-8-quinolinol 2,3 -dimethyl-8-quinolinol3,4-dimethyl-8-quinolinol 5-hexyl-8-quinolinol 6-methoxy-8-quinolinol7-propyl-8-quinolinol 5,6-quinolinediol 5,8-quinolinediol6,8-quinolinediol 2-methy1-7,8-quinolinediol In accordance with apreferred mode of carrying out this improved process, aqua ammonia isadded to an aqueous solution of sodium bisulfite until the mixture ispractically neutral, i.e., pH is just 7. Thereafter S-quinolinol inamount of about /3 mol. equivalent, is added to the mixture which thenis heated, in a stainless steel autoclave, at about to C., for about 24hours. The autogenous pressure developed ranges between 60 and 80p.s.i.g. Thereafter the mixture is cooled to ambient temperature and thesolid product is separated from the aqueous reaction mixture andpurified in a known manner, e.g., by steam distillation or by vacuumdistillation.

Although freshly-prepared sodium ammonium sulfite is the preferredaminating agent in this novel process, other agents can be used. Asexamples of such alternatives, the following are mentioned:

diammonium sulfite potassium ammonium sulfite magnesium ammonium sulfitecalcium ammonium sulfite strontium ammonium sulfite barium ammoniumsulfite Mixtures of these and equivalent agents are also contemplatedfor use in the process of the instant invention.

The absence of free ammonia from the reaction mixture of this novelprocess has the advantage of reducing substantially the corrosive attackof the mixture on the equipment and also permits the reaction tobecarried out at a considerably lower pressure. Inasmuch as equipmentdesigned to withstand high pressure is relatively expensive to installand maintain, it will be readily appreciated that the more modestpressures developed in the course of the improved reaction permits theuse of less expensive equipment and thus results in a considerableeconomic advantage.

This new process is carried out preferably in stainless steel equipmentsince the corrosion of such equipment by the reaction mixture isinsignificant. Various types of chromium/nickel steels can be usedincluding equipment fabricated in whole or in part from 304, 316, 317,347 and the like austenitic stainless steels. As will be obvious theequipment can be fabricated from more than one type, e.g., the autoclavecan be of 316 SS, the agitator from 347 SS, the piping from 304 SS, andthe valves from Hastelloy steel.

The temperature at which the amination is effected can be varied over awide range. Although it is preferred to operate at a temperature between140 and 160 C., the reaction can be run at temperatures as low as about100 C. and as high as 200 C. In the lower range, the reaction velocityis so slow as to be uneconomical whereas at temperatures in excess of200 C., an undesirable amount of corrosion takes place.

The amount of ammonium sulfite salt which is used can also be variedover a broad range. Although theoretically the quinolinol and ammoniumsulfite react in molecular equivalent amounts, i.e., one mol ofquinolinol requires 1 mol of diammonium sulfite or 1 mol of sodiumammonium sulfite, an excess of the ammoniating agent is preferably used.Normally, between two and five times the theoretical quantity of theaminating agent is used since the use of less than this amount givesundesirably low yields, while more than this amount (5 molecularequivalents) does not give significantly increased yields.

The invention will-be illustrated by the following examples in whichparts and percentages are by weight and temperatures are given indegrees centigrade. As will be obvious to those skilled in the art towhich this invention pertains, changes may be made in the details ofthese purely illustrative examples without departing from the scope orspirit of the invention.

Example 1 To a cold (5 C.) solution of 700 parts of sodium metabisulfitein 500 parts of water, 447 parts of 28% aqua ammonia are added slowly.The vigorous exothermic reaction causes the mass .to heat up to about 65C., and thereafter it is cooled to about 30 C. The mass is neutral toslightly acidic to nitrazine yellow. The slurry of sodium ammoniumsulfite thus obtained is transferred to a 316 stainless steel autoclaveand 290.4 parts of 8-quinolinol are added. The mixture is heated to andmaintained at 151 to 153 C., for 24 hours. The pressure developed in theautoclave during this reaction is between 63 and 76 p.s.i.g. The mixtureis cooled to ambient temperature and then removed from the autoclave asa thin slurry of finely divided greenish solid. The autoclave is rinsedwith 450 parts of water and the combined slurry and wash liquor isheated to 70 C., then agitated and cooled to about 25 C. The resultantslurry is filtered and the filter cake is washed with 3000 parts ofwater. The washed solids are reslurried in a mixture of 91.5 parts of 50C., B. aqueous caustic soda and 1750 parts of water. The slurry isheated to 70 C., and then cooled while agitating to about 25 C. Theresultant granular slurry is filtered and the filter cake is washedalkali free to nitrazine yellow with about 3000 parts of water. Thecrude 8-aminoquinoline (M.P. 56.0 to 56.5 C.) is distilled in vacuo andgives 209 parts of pure 8-aminoquinoline of *M.-P. 66.0 to 66.5" C.

The autoclave in which this reaction was carried out shows no etching,pitting, crevice attack or other evidence of corrosion. The corrosionrate is estimated to be 0.00054 inch per year (i.p.y.).

Example 2 In an analogous experiment in which a like amount of8-quinolinol is reacted with diammonium sulfite (prepared in situ from357 parts of aqua ammonia and 207 parts of sulfur dioxide) and freeammonia (357 parts of 28% aqua lamim-oinia) by heating this mixture for8 hours at 148 C. to 150 C., with the pressure varying between 136 and150 p.s.i.g. A yield of 209 parts of distilled 8- aminoquinoline, MJP.64.5 C. to 65 C., is obtained. However, the 316 stainless steelautoclave shows severe pitting and considerable etching. The corrosionrate is estimated to be 0.0442 i.p.y.

Example 3 The procedure of Example 2 above is repeated but omitting thesecond addition of aqua ammonia from the autoclave charge. The aminationstep is thus conducted in the'substantial absence of free ammonia. Thecharge is heated at 150 C. to 155 C., in this instance for 8 hours. Thepressure developed varies between 72 and 78 p.s.i.g. The yield ofS-aminoquinoline from this experiment is somewhat less (163 parts) thanthat obtained in the preceding experiments but in contrast to the severecorrosion noted in Experiment 2, no evidence of corrosion (i.e., nopitting, etching, -etc.,) can be detected in this experiment. Thecorrosion rate is estimated to be 0.0016 i.p.y.

It can thus be seen that an efficient and economical procedure for themanufacture of 8-aminoquinoline has been devised which process iscapable of being operated in stainless steel equipment without thesevere corrosion which characterized similar processes in which freeammonia was present.

My invention has been illustrated by several examples which include thebest mode known to me of carrying out the process of my invention. Itis, however, not to be limited to the details of these examples sincevarious alternate details, some of which have been disclosed in theabove description, can be made in the illustrative examples. Forexample, a catalyst such as copper powder, cupnous bromide and thelilne, can be used to fiacilihate the reaction. Other variations in theprocedure will be obvious to those skilled in this art and can be usedwithout departing from the scope or spirit of this invention which islimited only by the appended claims.

I claim:

1. The process of preparing an ar-aminoquinoline from the correspondingar-quinolinol which comprises the step of .heating at a temperature notabove 200 C. and under autogenous pressure a mixture of thear-quinolinol and, as the sole aminating agent, an ammonium salt ofsulfurous acid having the general formula lVI-(N I-L) 090 wherein Mstands for a member of the group consisting of the ammonium group,alkali metals and alkaline earth metals and x stands for an integerequal to the valence of M.

2. The process as described in claim 1 in which the ar-quinolinol is8-quinolinol.

3. The process as described in claim 1 in which the ammonium salt issodium ammonium sulfite.

References Cited by the Examiner Hartshorn et al.: J. Am. Chem. Soc.,vol. 68, 1562-3, (1946).

Kogan et al.: Chem. Abstracts, vol. 32, column 7031 (1938).

ALEX MAZEL, Primary Examiner.

HENRY =R. JILES, Examiner.

DONALD G. DAUS, Assistant Examiner,

1. THE PROCESS OF PREPARING AN AR-AMINOQUINOLINE FROM THE CORRESPONDINGAR-QUINOLINOL WHICH COMRPRISES THE STEP OF HEATING AT A TEMPERATUER NOTABOVE 200*C. AND UNDER AUTOGENOUS PRESSURE A MIXTUE OF THE AR-QUINOLINOLAND, AS THE SOLE AMINATING AGENT, AN AMMONIUM SALT OF SULFUROUS ACIDHAVING THE GENERAL FORMULA M(NH4)X(SO3)X WHEREIN M STANDS FOR A MEMBEROF THE GROUP CONSISTING OF THE AMMONIUM GROUP, ALKALI METALS ANDALKALINE EARTH METALS AND X STANDS FOR AN INTGEGER EQUAL TO THE VALENCEOF M.